Conventional methods for synthesis of fluoroaromatic compounds are based on direct substitution of the hydrogen atoms or suitable functional groups of the aromatic ring with fluorine of a fluorinating agent. U.S. Pat. No. 3,499,942 discloses an alternative method of preparing aromatic compounds using a fluorosynthon.
2-chloro-4,5-difluorobenzoyl chloride which is normally prepared from 2-chloro-4,5-difluorobenzoic acid is used as a particularly valuable intermediate for synthesis of quinolone carboxylic acids which have a strong antibiotic activity.
U.S. Pat. No. 4,374,266 discloses fluorophthalamic acids and ammonium salts thereof, and a method for the preparation of these compounds. U.S. Pat. No. 5,003,103 discloses a preparation of 2-chloro-4,5-difluorobenzoic acid which is prepared by decarboxylating 4,5-difluorophthalic anhydride or 4,5-difluorophthalic acid to form 3,4-difluorobenzoic acid in N-methyl-2-pyrrolidone, quinoline, or dimethyl acetamide, treating the 3,4-difluorobenzoic acid with a mixture of nitric and sulfuric acids to produce 2-nitro-4,5-difluorobenzoic acid, and treating the 2-nitro-4,5-difluorobenzoic acid with elemental chlorine. European Patent Publication No. 431 373 A2 discloses a process for producing 5-fluorbenzoic acids which comprises trichloromethylating a fluorobenzene to obtain a 5-fluorobenzotrichloride, reacting with aqueous ammonia to obtain a 5-fluorobenzonitrile, reacting with a fluorinating agent to obtain a 5-fluorobenzonitrile, and hydrolyzing it. However, all of these methods have shortcomings of either longer reaction steps or using expensive reagents.
Generally, the 2-chloro-4,5-difluorobenzoyl chloride has been prepared by reacting 2-chloro-4,5-difluorobenzoic acid with thionyl chloride.
U.S. Pat. No. 4,754,084 discloses a preparation of substituted fluorobenzenes which is produced by pyrolyzing vinylfluorocyclobutanes in the presence of activated carbon or certain metal oxides or mixtures of metal oxides. In this invention, a tetrafluoroethylene was used to prepare the substituted fluorobenzenes, which tends to polymerize spontaneously in the presence of traces of oxygen. Therefore, the tetrafluoroethylene should be stored at low temperature without contacting air. In the pyrolysis of vinylfluorocyclobutane derivatives, it forms easily polymeric by-products which affects badly a yield of products and cause difficulties in mass production, thus it is always required to react in a nitrogen gas atmosphere.
In addition, the methods described above have a difficulty for isolation of the desired product because of formation of structurally similar by-products.
Accordingly, to overcome the shortcomings as described above, the present inventors have developed methods of preparing 2-chloro-4,5-difluorobenzoic acid and 2-chloro-4,5-difluorobenzoyl chloride without passing via vinylfluorocyclobutane derivatives.